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Sulfonylurea

Glimepiride

Approved 22 Sept 2009OralTablet

The FDA lists this product in 55 strengths and forms.

Indications

Glimepiride Tablet, USP is indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus [see Clinical Studies ( 14.1 )] ]. Glimepiride Tablet USP is a sulfonylurea indicated as an adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus ( 1.1 ). Important Limitations of Use: Not for treating type 1 diabetes mellitus or diabetic ketoacidosis ( 1.1 ).

1.1Important Limitations of Use

Glimepiride should not be used for the treatment of type 1 diabetes mellitus or diabetic ketoacidosis, as it would not be effective in these settings.

Contraindications

Glimepiride is contraindicated in patients with a history of a hypersensitivity reaction to: Glimepiride or any of the product's ingredients [ see Warnings and Precautions ( 5.2 ) ]. Sulfonamide derivatives: Patients who have developed an allergic reaction to sulfonamide derivatives may develop an allergic reaction to Glimepiride. Do not use glimepiride in patients who have a history of an allergic reaction to sulfonamide derivatives.

Reported hypersensitivity reactions include cutaneous eruptions with or without pruritus as well as more serious reactions (e.g. anaphylaxis, angioedema, Stevens-Johnson Syndrome, dyspnea) [ see Warnings and Precautions ( 5.2 ) and Adverse Reactions ( 6.2 ) ]. Hypersensitivity to glimepiride or any of the product's ingredients ( 4 ) Hypersensitivity to sulfonamide derivatives ( 4 )

Warnings and precautions

Hypoglycemia: May be severe. Ensure proper patient selection, dosing, and instructions, particularly in at-risk populations (e.g., elderly, renally impaired) and when used with other anti-diabetic medications ( 5.1 ). Hypersensitivity Reactions: Post-marketing reports include anaphylaxis, angioedema and Stevens-Johnson Syndrome. Promptly discontinue glimepiride, assess for other causes, institute appropriate monitoring and treatment, and initiate alternative treatment for diabetes ( 5.2 ).

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Interactions

Certain medications may affect glucose metabolism, requiring glimepiride dose adjustment and close monitoring of blood glucose ( 7.1 ). Miconazole: Severe hypoglycemia can occur when glimepiride and oral miconazole are used concomitantly. ( 7.2 ). Cytochrome P450 2C9 interactions: Inhibitors and inducers of cytochrome P450 2C9 may affect glycemic control by altering glimepiride plasma concentrations ( 7.3 ). Colesevelam: Coadministration may reduce glimepiride absorption.

Glimepiride should be administered at least 4 hours prior to colesevelam ( 2.1 , 7.4 ).

7.1Drugs Affecting Glucose Metabolism

A number of medications affect glucose metabolism and may require glimepiride dose adjustment and particularly close monitoring for hypoglycemia or worsening glycemic control. The following are examples of medications that may increase the glucose-lowering effect of sulfonylureas including glimepiride, increasing the susceptibility to and/or intensity of hypoglycemia: oral anti-diabetic medications, pramlintide acetate, insulin, angiotensin converting enzyme (ACE) inhibitors, H2 receptor antagonists, fibrates, propoxyphene, pentoxifylline, somatostatin analogs, anabolic steroids and androgens, cyclophosphamide, phenyramidol, guanethidine, fluconazole, sulfinpyrazone, tetracyclines, clarithromycin, disopyramide, quinolones, and those drugs that are highly protein-bound, such as fluoxetine, nonsteroidal anti-inflammatory drugs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid and monoamine oxidase inhibitors.

When these medications are administered to a patient receiving glimepiride, monitor the patient closely for hypoglycemia. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for worsening glycemic control. The following are examples of medications that may reduce the glucose-lowering effect of sulfonylureas including glimepiride, leading to worsening glycemic control: danazol, glucagon, somatropin, protease inhibitors, atypical antipsychotic medications (e.g., olanzapine and clozapine), barbiturates, diazoxide, laxatives, rifampin, thiazides and other diuretics, corticosteroids, phenothiazines, thyroid hormones, estrogens, oral contraceptives, phenytoin, nicotinic acid, sympathomimetics (e.g., epinephrine, albuterol, terbutaline), and isoniazid.

When these medications are administered to a patient receiving glimepiride, monitor the patient closely for worsening glycemic control. When these medications are withdrawn from a patient receiving glimepiride, monitor the patient closely for hypoglycemia. Beta-blockers, clonidine, and reserpine may lead to either potentiation or weakening of glimepiride's glucose-lowering effect. Both acute and chronic alcohol intake may potentiate or weaken the glucose-lowering action of glimepiride in an unpredictable fashion.

The signs of hypoglycemia may be reduced or absent in patients taking sympatholytic drugs such as beta-blockers, clonidine, guanethidine, and reserpine.

7.2Miconazole

A potential interaction between oral miconazole and sulfonylureas leading to severe hypoglycemia has been reported. Whether this interaction also occurs with other dosage forms of miconazole is not known.

7.3Cytochrome P450 2C9 Interactions

There may be an interaction between glimepiride and inhibitors (e.g., fluconazole) and inducers (e.g., rifampin) of cytochrome P450 2C9. Fluconazole may inhibit the metabolism of glimepiride, causing increased plasma concentrations of glimepiride which may lead to hypoglycemia. Rifampin may induce the metabolism of glimepiride, causing decreased plasma concentrations of glimepiride which may lead to worsening glycemic control.

7.4Concomitant Administration of Colesevelam

Colesevelam can reduce the maximum plasma concentration and total exposure of glimepiride when the two are coadministered. However, absorption is not reduced when glimepiride is administered 4 hours prior to colesevelam. Therefore, glimepiride should be administered at least 4 hours prior to colesevelam.

Adverse reactions

The following serious adverse reactions are discussed in more detail below and elsewhere in the labeling: Hypoglycemia [see Warnings and Precautions ( 5.1 ) ] Hemolytic anemia [see Warnings and Precautions ( 5.3 ) ] In clinical trials, the most common adverse reactions with glimepiride were hypoglycemia, dizziness, asthenia, headache, and nausea. Common adverse reactions in clinical trials (≥5% and more common than with placebo) include hypoglycemia, headache, nausea, and dizziness ( 6.1 ).

To report SUSPECTED ADVERSE REACTIONS, contact Carlsbad Technology, Inc. at (760) 431-8284 or contact FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

6.1Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. Approximately 2,800 patients with type 2 diabetes have been treated with glimepiride in the controlled clinical trials. In these trials, approximately 1,700 patients were treated with glimepiride for at least 1 year.

Table 1 summarizes adverse events, other than hypoglycemia, that were reported in 11 pooled placebo-controlled trials, whether or not considered to be possibly or probably related to study medication. Treatment duration ranged from 13 weeks to 12 months. Terms that are reported represent those that occurred at an incidence of ≥5% among glimepiride -treated patients and more commonly than in patients who received placebo.

Table 1. Eleven Pooled Placebo-Controlled Trials ranging from 13 weeks to 12 months: Adverse Events (Excluding Hypoglycemia) Occurring in ≥5% of glimepiride -treated Patients and at a Greater Incidence than with Placebo* *Glimepiride doses ranged from 1-16 mg administered daily †Insufficient information to determine whether any of the accidental injury events were associated with hypoglycemia Glimepiride N=745 % Placebo N=294 % Headache 8.2

7.8Accidental

Injury † 5.8

3.4 Flu Syndrome 5.4

4.4 Nausea 5.0

3.4 Dizziness 5.0

2.4 Hypoglycemia: In a randomized, double-blind, placebo-controlled monotherapy trial of 14 weeks duration, patients already on sulfonylurea therapy underwent a 3-week washout period then were randomized to glimepiride 1 mg, 4 mg, 8 mg or placebo. Patients randomized to glimepiride 4 mg or 8 mg underwent forced-titration from an initial dose of 1 mg to these final doses, as tolerated [see Clinical Studies ( 14.1 )]. The overall incidence of possible hypoglycemia (defined by the presence of at least one symptom that the investigator believed might be related to hypoglycemia; a concurrent glucose measurement was not required) was 4% for glimepiride 1 mg, 17% for glimepiride 4 mg, 16% for glimepiride 8 mg and 0% for placebo.

All of these events were self-treated. In a randomized, double-blind, placebo-controlled monotherapy trial of 22 weeks duration, patients received a starting dose of either 1 mg glimepiride or placebo daily. The dose of glimepiride was titrated to a target fasting plasma glucose of 90-150 mg/dL. Final daily doses of glimepiride were 1, 2, 3, 4, 6 or 8 mg [S ee Clinical Studies ( 14.1 )] . The overall incidence of possible hypoglycemia (as defined above for the 14-week trial) for glimepiride vs. placebo was 19.7% vs. 3.2%.

All of these events were self-treated. Weight gain: Glimepiride, like all sulfonylureas, can cause weight gain [see Clinical Studies ( 14.1 ) ]. Allergic Reactions: In clinical trials, allergic reactions, such as pruritus, erythema, urticaria, and morbilliform or maculopapular eruptions, occurred in less than 1% of glimepiride -treated patients. These may resolve despite continued treatment with glimepiride. There are post-marketing reports of more serious allergic reactions (e.g., dyspnea, hypotension, shock) [see Warnings and Precautions ( 5.2 ). ].

Laboratory Tests: Elevated Serum Alanine Aminotransferase (ALT): In 11 pooled placebo-controlled trials of glimepiride, 1.9% of glimepiride -treated patients and 0.8% of placebo-treated patients developed serum ALT greater than 2 times the upper limit of the reference range.

6.2Post-marketing Experience

The following adverse reactions have been identified during post-approval use of glimepiride. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Serious hypersensitivity reactions, including anaphylaxis, angioedema, and Stevens-Johnson Syndrome [see Warnings and Precautions ( 5.2 ) ] Hemolytic anemia in patients with and without G6PD deficiency [see Warnings and Precautions ( 5.3 ) ] Impairment of liver function (e.g. with cholestasis and jaundice), as well as hepatitis, which may progress to liver failure.

Porphyria cutanea tarda, photosensitivity reactions and allergic vasculitis Leukopenia, agranulocytosis, aplastic anemia, and pancytopenia Thrombocytopenia (including severe cases with platelet count less than 10,000/μL) and thrombocytopenic purpura Hepatic porphyria reactions and disulfiram-like reactions Hyponatremia and syndrome of inappropriate antidiuretic hormone secretion (SIADH), most often in patients who are on other medications or who have medical conditions known to cause hyponatremia or increase release of antidiuretic hormone

Glimepiride

Indications

1.1Important Limitations of Use

Contraindications

Warnings and precautions

Two medicines in one question?

5.1Hypoglycemia

5.2Hypersensitivity Reactions

5.3Hemolytic Anemia

5.4Increased Risk of Cardiovascular Mortality with Sulfonylureas

5.5Macrovascular Outcomes

Interactions

7.1Drugs Affecting Glucose Metabolism

7.2Miconazole

7.3Cytochrome P450 2C9 Interactions

7.4Concomitant Administration of Colesevelam

Pregnancy and breastfeeding

8.1Pregnancy Pregnancy Category C

Adverse reactions

6.1Clinical Trials Experience

7.8Accidental

6.2Post-marketing Experience

Composition

Strengths and forms

Official product information

At a glance

Guidelines